New Phase 3 Data Support Potential First-in-Class Orexin-Based Treatment for Narcolepsy Type 1

Takeda presented data from two global phase 3 trials of oveporexton (TAK-861), an investigational oral orexin receptor 2–selective agonist, demonstrating statistically significant and clinically meaningful improvements across multiple symptoms of narcolepsy type 1 (NT1). The findings were shared during oral presentations at the World Sleep 2025 Congress in Singapore.¹

The results come from the FirstLight (TAK-861-3001) and RadiantLight (TAK-861-3002) studies, both randomized, double-blind, placebo-controlled trials evaluating oveporexton in adults with NT1.^2,3 Across both studies, all primary and secondary end points were met, with p values of <0.001 for all doses (twice-daily 1 mg and twice-daily 2 mg) compared with placebo at week 12.¹

According to Takeda, oveporexton was generally well tolerated, with a safety profile consistent with prior studies. No serious treatment-related adverse events were reported. The most common adverse events were insomnia, urinary urgency, and urinary frequency, most of which were mild to moderate in severity.¹

NT1 is a rare, chronic neurologic disorder caused by the loss of orexin-producing neurons, leading to excessive daytime sleepiness, cataplexy, and other disabling symptoms. Currently available therapies address individual symptoms but do not target the underlying orexin deficiency. Oveporexton is designed to restore orexin signaling by selectively activating orexin receptor 2.⁴

In the phase 3 program, 273 patients from 19 countries were enrolled across both studies, with 14 primary and secondary end points assessed over 12 weeks. More than 95% of participants who completed the trials entered an ongoing long-term extension study.¹

Efficacy outcomes presented at World Sleep included improvements in wakefulness, cataplexy, symptom severity, and quality of life. For wakefulness, oveporexton significantly improved mean sleep latency on the Maintenance of Wakefulness Test and Epworth Sleepiness Scale scores compared with placebo at week 12. The majority of participants receiving the twice-daily 2 mg dose achieved wakefulness within the normative range (≥20 minutes) on the Maintenance of Wakefulness Test, and close to 85% achieved Epworth Sleepiness Scale scores ≤10.¹

Cataplexy outcomes showed a median reduction in weekly cataplexy rate of more than 80% from baseline across doses compared with placebo. Median cataplexy-free days increased from 0 days at baseline to 4 to 5 days per week at week 12.¹

Symptom severity, assessed using the Narcolepsy Severity Scale total score, improved significantly versus placebo, with more than 70% of participants reporting mild disease severity (score 0–14). Nearly all treated participants (97%) reported improvement on the Patient Global Impression of Change scale.¹

Quality-of-life measures also improved significantly. Scores on the Short Form-36-item survey reached the normative range, with supportive findings from exploratory analyses using the EuroQol 5-Dimension 5-Level instrument.¹

FirstLight enrolled 168 participants randomized to twice-daily 2 mg, twice-daily 1 mg, or placebo, while RadiantLight enrolled 105 participants randomized to twice-daily 2 mg or placebo. In both studies, the primary end point was improvement in excessive daytime sleepiness as measured by the Maintenance of Wakefulness Test. Key secondary end points included Epworth Sleepiness Scale scores and weekly cataplexy rate.

“Our research has shown that the loss of orexin is the cause of narcolepsy type 1, which results in symptoms like excessive daytime sleepiness and cataplexy,” Emmanuel Mignot, MD, PhD, principal investigator for the FirstLight Phase 3 study, said in a press release. “Takeda’s groundbreaking efforts targeting the orexin receptor 2 in clinical studies led to positive Phase 3 results for oveporexton, bringing us a major step closer to having the first orexin therapy that addresses the underlying cause of narcolepsy type 1—with the potential of transforming the current treatment paradigm.”¹

Narcolepsy often overlaps with or affects psychiatric disorders as well.⁵ Diagnosis can be complex, and symptoms can be misattributed to a psychiatric disorder or narcolepsy. Takeda has begun an ongoing long term extension study to further investigate the long-term effects of oveporexton. The company plans to submit global regulatory applications for oveporexton starting in fiscal year 2025.

References:

1. Takeda presents orexin data from landmark oveporexton (Tak-861) phase 3 program in narcolepsy type 1 at World Sleep 2025. Press release. September 8, 2025. Accessed September 10, 2025. https://www.takeda.com/newsroom/newsreleases/2025/takeda-orexin-data-oveporexton-phase-3-narcolepsy-world-sleep-2025/

2. A study of TAK-861 for the treatment of narcolepsy type 1. ClinicalTrials.gov. July 1, 2025. Accessed September 10, 2025. https://clinicaltrials.gov/study/NCT06470828

3. A study of TAK-861 in people with narcolepsy type 1. ClinicalTrials.gov. July 2, 2025. Accessed September 10, 2025. https://clinicaltrials.gov/study/NCT06505031

4. Dauvilliers Y, Plazzi G, Mignot E, et al. Oveporexton, an oral orexin receptor 2-selective agonist, in narcolepsy type 1. N Engl J Med. 2025;392(19):1905-1916.

5. Mariman An, Jan LG. The symptom masquerade: narcolepsy or a psychiatric disorder? Intl J Clin Stu Med Rep. 2025;55:1360.